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Fc-engineered CD37 monoclonal antibody
BI 836826* is an immunoglobulin G (IgG1) CD37 monoclonal antibody (mAb) that mediates antibody-dependent cellular cytotoxicity (ADCC) and has pro-apoptotic activity.1 In March 2017, the FDA granted Orphan Drug Designation to BI 836826 for the treatment of chronic lymphoid leukaemia (CLL). Several Phase I and Ib/II clinical trials investigating BI 836826 as monotherapy or in combination are ongoing in CLL and in non-Hodgkin lymphoma (NHL).2-6
About BI 836826
BI 836826’s mechanism of action
BI 836826 is a chimeric mouse-human mAb that targets human CD37. It has a dual mode of action: it has been engineered to increase binding affinity to the Fcƴ receptors (FcƴRIIIa) on effector cells by replacing two amino acids in the Fc region for improved ADCC,1 and in addition, it has intrinsic pro-apoptotic activity.1
The role of CD37
CD37 is a leukocyte-specific cell surface protein, expressed on B and T lymphocytes, monocytes, macrophages, neutrophils and dendritic cells.7 CD37 is a member of the tetraspanin family and plays a role in cellular signalling to other membrane proteins in order to modulate cellular adhesion, motility and proliferation.7,8 High levels of CD37 are found on mature B-cell leukaemia and lymphoma cells8,9 which makes it a potential target for therapeutic antibodies.1
Preclinical studies have shown BI 836826 to have higher ADCC and apoptotic activity in Ramos and CLL cells in vitro and to efficiently deplete CLL cells in whole blood samples ex vivo when compared with the anti-CD20 mAb rituximab.1,10,11 Preclinical combination studies of BI 836826 with chemotherapy, rituximab or the phosphoinositide 3-kinase (PI3K) inhibitor idelalisib have shown improved efficacy against lymphoma cells and improved efficacy in a murine xenograft model of human B cell lymphoma.1,10,12,13
Preliminary data suggested that the combination of BI 836826 and idelalisib enhanced direct cytotoxicity in high-risk CLL patients.14 In phase I trials, tolerable doses for BI 836826 in relapsed/refractory CLL (trial 1270.1)4,15 and NHL (trial 1270.2)6,16 were determined, and BI 836826 showed promising signs of clinical activity.15,16
BI 836826 is currently being investigated in Phase I/II studies, both as monotherapy and in combination with established therapies, in patients with CLL,2,4,5,15 non-Hodgkin’s lymphoma of B-cell origin (B-NHL)6,16 and diffuse large B-cell lymphoma (DLBCL).3
AE, adverse event; B-NHL, non-Hodgkin’s lymphoma of B-cell origin; CLL, chronic lymphoid leukaemia; DLBCL, diffuse large B-cell lymphoma; DLT, dose-limiting toxicity; MRD, minimal residual disease; MTD, maximum tolerated dose; PFS, progression-free survival.
Heider KH, et al. Blood 2011;118(15):4159–68.
ClinicalTrials.gov. NCT02759016. https://clinicaltrials.gov/ct2/show/NCT02759016 (Accessed: July 2017).
ClinicalTrials.gov. NCT02624492. https://clinicaltrials.gov/ct2/show/NCT02624492 (Accessed: July 2017).
ClinicalTrials.gov. NCT01296932. https://clinicaltrials.gov/ct2/show/NCT01296932 (Accessed: July 2017).
ClinicalTrials.gov. NCT02538614. https://clinicaltrials.gov/ct2/show/NCT02538614 (Accessed: July 2017).
ClinicalTrials.gov. NCT01403948. https://clinicaltrials.gov/ct2/show/NCT01403948 (Accessed: July 2017).
van Spriel AB, et al. J Immunol 2004;172(5):2953–61.
Barrena S, et al. Leukemia 2005;19(8):1376–83.
Belov L, et al. Cancer Res 2001;61(11):4483–9.
Krause G, et al. Br J Haematol 2016;173(5):791–4.
Krause G, et al. Leukemia 2012;26(3):546-9.
Heider K-H, et al. Poster presented at EHA 2012; Abstract 185.
Baki I, et al. Poster presented at EHA 2012; Abstract R12-2660.
Stephens DM, et al. Blood 2014;124(21):4681.
Stilgenbauer S, et al. Haematologica 2015;100(Suppl 1):225–6;Abstract P589.
Kroschinsky F, et al. Presented at the 13th International Conference on Malignant Lymphoma 2015; Abstract 286.
*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.
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